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Human Genetics

, Volume 115, Issue 4, pp 319–326 | Cite as

Genomic rearrangements at the IGHMBP2 gene locus in two patients with SMARD1

  • Ulf P. Guenther
  • Markus SchuelkeEmail author
  • Enrico Bertini
  • Adele D’Amico
  • Nathalie Goemans
  • Katja Grohmann
  • Christoph Hübner
  • Raymonda Varon
Original Investigation

Abstract

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by mutations in the immunoglobulin μ-binding protein 2 (IGHMBP2) gene. Patients affected by the infantile form of SMARD1 present with early onset respiratory distress. So far, patients with neither juvenile onset nor with larger deletions/rearrangements in IGHMBP2 have been reported. In this study, we investigated one patient with infantile (4 months) and another with juvenile (4.3 years) onset of respiratory distress. Direct sequencing of all exons and flanking intron sequences in both patients revealed a mutation on only one allele. In both patients, we identified genomic rearrangements of the other allele of IGHMBP2 by means of Southern blotting. Putative breakpoints were confirmed by polymerase chain reaction on genomic and cDNA. The patient with juvenile onset had an Alu/Alu mediated rearrangement, which resulted in the loss of ~18.5 kb genomic DNA. At the mRNA level, this caused an in-frame deletion of exons 3–7. The patient with infantile onset had a complex rearrangement with two deletions and an inversion between intron 10 and 14. This rearrangement led to a frameshift at the mRNA level. Our results show that SMARD1 can be caused by genomic rearrangements at the IGHMBP2 gene locus. This may be missed by mere sequence analysis. Additionally, we demonstrate that juvenile onset SMARD1 may also be caused by mutations of IGHMBP2. The complex nature of the genomic rearrangement in the patient with infantile SMARD1 is discussed and a deletion mechanism is proposed.

Keywords

Compound Muscle Action Potential Illegitimate Recombination Juvenile Onset Diaphragmatic Paralysis Breakpoint Junction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank the patients for their participation in this study and Angela M. Kaindl and Martin Digweed for critically reading the manuscript. The technical assistance of Cathrin Janetzki and Marco Kohlmeyer’s help to create Fig. 4C–F are gratefully acknowledged. This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; HU 408/3-2 to C.H. and R.V.) and by the parents’ support group (“Helft dem muskelkranken Kind, e.V.”, Hamburg, Germany, C.H.).

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ulf P. Guenther
    • 1
    • 2
  • Markus Schuelke
    • 1
    Email author
  • Enrico Bertini
    • 3
  • Adele D’Amico
    • 3
  • Nathalie Goemans
    • 4
  • Katja Grohmann
    • 1
  • Christoph Hübner
    • 1
  • Raymonda Varon
    • 2
  1. 1.Department of NeuropediatricsCharité University Medical School of BerlinBerlinGermany
  2. 2.Institute of Human GeneticsCharité University Medical School of BerlinBerlinGermany
  3. 3.Department of Neuroscience and Unit of Molecular MedicineBambino Gesù Children’s HospitalRomeItaly
  4. 4.University Children’s HospitalLeuvenBelgium

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